GleghornLab/Signor_2class · Datasets at Hugging Face

IdA string	IdB string	labels int64	mechanism string	effect string	score float64	sentence string	signor_id string
P10451	Q13950	0	transcriptional regulation	up-regulates quantity	0.488	Ets-1 and Runx2 are critical transcriptional regulators of OPN expression in CT26 colorectal cancer cells. Suppression of these transcription factors results in significant down-regulation of the OPN metastasis protein.	SIGNOR-245336
P43403	P06241	0	phosphorylation	up-regulates activity	0.574	Subsequently, Lck and Fyn phosphorylate and activate the Syk family kinase ZAP-70 when it is recruited to the phosphorylated ITAM motifs xref .	SIGNOR-279043
P52292	Q09472	0	acetylation	up-regulates	0.357	Ampk triggered the acetylation of importin alpha1 on lys(22), a process dependent on the acetylase activity of p300	SIGNOR-128625
O14733	Q13233	0	phosphorylation	up-regulates	0.723	Here we show that jnkk2, a novel member of the map kinase kinase family, was phosphorylated and activated by mekk1	SIGNOR-51207
Q9UKX5	Q02447	0	null	up-regulates quantity by expression	0.2	We speculate that the "mesenchymal signature" of alpha11 integrin gene expression is controlled by the activity of Sp1/Sp3, fibroblast-specific combinations of Ets family members and yet unidentified enhancer-binding transcription factors.	SIGNOR-253351
O14770	P42771	1	transcriptional regulation	up-regulates quantity by expression	0.2	We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4.	SIGNOR-267240
P19525	Q9NYA1	1	phosphorylation	up-regulates activity	0.2	This suggests that PKR is critical in the phosphorylation of SPHK1 at Ser225.\|We confirmed that phosphorylated PKR activates SPHK1 kinase activity, but it remained necessary to determine whether there has mutual correlation or any reciprocal effect between these two kinases in stressed cells.	SIGNOR-278514
Q5S007	P61026	1	phosphorylation	down-regulates activity	0.33	To investigate whether the phosphorylation of Rab10 by LRRK2 is direct, we performed an in vitro kinase assay using recombinant components. Notably, we found that both wt and LRRK2-G2019S, but neither kinase inactive D1994A mutant nor small molecule-inhibited LRRK2, efficiently phosphorylated Rab10, proving a direct kinase-substrate relationship (Figure 2C). Furthermore, incubation of Rab10 with LRRK2 followed by tryptic digestion and MS analysis unambiguously identified T73 as the major phosphorylation site (Figure 2—figure supplement 1B)\|In pathogenic conditions, in which LRRK2 is hyperactive, RabGTPases have strongly diminished affinities for GDIs.	SIGNOR-261277
P53778	Q13424	1	phosphorylation	up-regulates	0.668	Sapk3 phosphorylates alpha1-syntrophin at serine residues 193 and 201 in vitro and phosphorylation is dependent on binding to the pdz domain of alpha1-syntrophin. The finding that sapk3 co-localizes with _1-syntrophin in skeletal muscle, that it binds to the pdz domain of _1-syntrophin, and that phosphorylation of _1-syntrophin depends on this interaction identifies a novel mechanism for targeting a protein kinase to its substrates.	SIGNOR-67061
P50613	Q9NYV4	1	phosphorylation	up-regulates activity	0.51	Although Cdk12/CycK kinase complex lacking T-loop phosphorylation showed some basal activity towards a CTD substrate prephosphorylated at position Ser7, its activity was significantly increased upon coexpression with the CAK from S. cerevisiae (Supplementary Fig. 9a). Mutation of T893 to E to mimic phosphorylation showed no effect on basal kinase activity. Quantitative phosphorylation of a single residue occurred upon coexpression with Cak1, as determined by ESI mass spectrometry (Supplementary Fig. 9b).	SIGNOR-275509
P10644	P24941	0	phosphorylation	up-regulates	0.343	In this context, we have identified rialpha as a novel substrate for the g(1)/s-cyclin-dependent kinase, cdk2/cyclin e, and found that rialpha is specifically phosphorylated at the serine residue.	SIGNOR-145577
B2RTY4	P61586	1	gtpase-activating protein	down-regulates activity	0.565	We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)\|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs\| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).	SIGNOR-260508
P00540	Q02750	1	phosphorylation	up-regulates activity	0.485	Our data indicate that Mos activated MEK1 in vitro as well as in vivo by phosphorylating Ser 222.	SIGNOR-260920
Q96J02	Q7Z434	1	ubiquitination	down-regulates quantity by destabilization	0.646	These data collectively indicate that AIP4 is the E3 ligase for MAVS.\|We generated single substitutions (K362A, K371A or K420A) and combined point substitutions of MAVS and tested their degradation. K371A or K420A MAVS showed partial resistance to PCBP2-induced degradation (data not shown), whereas MAVS with the combined substitutions K371A and K420A (KK-AA) completely withstood the degradation	SIGNOR-260362
Q96DX5	P12277	1	polyubiquitination	down-regulates quantity by destabilization	0.683	We demonstrate that creatine kinase B (CKB) interacts with Asb-9 in a specific, SOCS box-independent manner. This interaction increases the polyubiquitylation of CKB and decreases total CKB levels within the cell. The targeting of CKB for degradation by Asb-9 was primarily SOCS box-dependent and suggests that Asb-9 acts as a specific ubiquitin ligase regulating levels of this evolutionarily conserved enzyme.	SIGNOR-271623
Q9UKX2	Q14814	0	transcriptional regulation	up-regulates quantity by expression	0.327	Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation	SIGNOR-238712
O14757	P12830	1	phosphorylation	down-regulates activity	0.301	Phosphorylation of Cdh1 by Chk1 promotes recognition of Cdh1 by SCF betaTRCP1.\|These data suggest that Chk1 negatively regulates APC/C Cdh1 activity by both promoting Cdh1 destruction and by destabilizing its association with the APC/C.	SIGNOR-278396
P36897	P29353	1	phosphorylation	up-regulates	0.548	We now report that upon TGF-_ stimulation, T_RI phosphorylates ShcA on serine and, to a lesser degree, on tyrosine to activate Erk MAP kinases.	SIGNOR-227503
P29350	P32927	1	dephosphorylation	down-regulates	0.522	However, inhibition of shp2 binding to betac, did not prevent tyrosine phosphorylation of shp2. Interestingly, this same phosphopeptide served as a substrate for the tyrosine phosphatase activity of both shp1 and shp2.	SIGNOR-114597
O00743	Q8N884	1	dephosphorylation	down-regulates activity	0.2	In this study, we found that PPP6C suppressed phosphorylation of human cGAS (hcGAS) at S435 or mouse cGAS (mcGAS) at S420 in its substrate-binding pocket, thus preventing its binding to GTP and inhibiting the synthesis of cGAMP.\|These data suggest that PPP6C inhibits cGAS activity.	SIGNOR-276990
P12931	O15524	1	phosphorylation	down-regulates activity	0.45	SOCS1 is phosphorylated on Y80 by SRC family kinase members SRC and YES1.	SIGNOR-276857
P46937	P31749	0	phosphorylation	down-regulates	0.593	One protein that associates with 14-3-3 in an akt-dependent manner is shown here to be the yes-associated protein (yap), which is phosphorylated by akt at serine 127, leading to binding to 14-3-3. Akt promotes yap localization to the cytoplasm, resulting in loss from the nucleus where it functions as a coactivator of transcription factors including p73.	SIGNOR-252593
P31645	P12931	0	phosphorylation	up-regulates quantity by stabilization	0.258	We found that 1) SERT exists in a tyrosine-phosphorylated form, 2) inhibition of tyrosine kinase(s) reduces SERT expression levels by facilitating SERT protein degradation, 3) Src-kinase activity up-regulates SERT protein expression with a concomitant increase in 5-HT uptake and tyrosine phosphorylation, and 4) mutation of Tyr47 or Tyr142 abolishes src-induced increases in transport function and phosphorylation of SERT.	SIGNOR-276386
P50549	Q15418	0	phosphorylation	up-regulates activity	0.35	Here we describe that the 90-kDa ribosomal S6 kinase 1 (RSK1), a protein kinase downstream of the extracellular signal-regulated kinase (ERK) subclass of MAPKs, binds to ER81, phosphorylates it, and enhances ER81-dependent transcription. Two in vivo RSK1 phosphorylation sites within ER81, Ser(191) and Ser(216), were identified, whose mutation to alanine reduces ER81 activity upon ERK-MAPK stimulation.	SIGNOR-249163
O95398	P62834	1	guanine nucleotide exchange factor	up-regulates activity	0.71	Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well.	SIGNOR-263956
O60936	P68400	0	phosphorylation	up-regulates activity	0.324	Phosphorylation of ARC at T149 Is Required for Its Antiapoptotic Effect. Here we report that the function of ARC is regulated by protein kinase CK2. ARC at threonine 149 is phosphorylated by CK2. This phosphorylation targets ARC to mitochondria. ARC is able to bind to caspase-8 only when it is localized to mitochondria but not to the cytoplasm.	SIGNOR-262837
P31749	Q9BRS8	1	phosphorylation	up-regulates activity	0.353	Akt dependent phosphorylation of LARP6. We provide the first description that LARP6 is phosphorylated at multiple sites and that phosphorylation of S451 is critical to activate the protein in type I collagen biosynthesis.	SIGNOR-277213
P00519	Q99638	1	phosphorylation	up-regulates activity	0.477	The SH3 domain of c-Abl interacts directly with the C-terminal region of Rad9. c-Abl phosphorylates the Rad9 Bcl-2 homology 3 domain (Tyr-28) in vitro and in cells exposed to DNA-damaging agents. \| c-Abl-mediated phosphorylation of Rad9 induces binding of Rad9 to Bcl-xL \|these findings indicate that Rad9 is regulated by a c-Abl-dependent mechanism in the apoptotic response to genotoxic stress.	SIGNOR-260843
Q13443	P50281	0	cleavage	down-regulates quantity by destabilization	0.341	Here we show that MT1-MMP forms a complex with FGFR2 and ADAM9 in osteoblasts and proteolytically inactivates ADAM9\|Western blotting using antibodies against ectodomain of ADAM9 detected a fragment (around 26 kDa) of ADAM9 in the conditioned culture medium from cells cotransfected with wild-type MT1-MMP, but not in that with catalytic activity-dead MT1-MMP (Figure 6A, top).	SIGNOR-260301
P04637	P06493	0	phosphorylation	up-regulates activity	0.579	The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A	SIGNOR-167779
P05771	Q14847	1	phosphorylation	down-regulates activity	0.2	Actin binding of human lim and sh3 protein is regulated by cgmp- and camp-dependent protein kinase phosphorylation on serine 146. Phosphorylation of lasp at ser-146 leads to a redistribution of the actin-bound protein from the tips of the cell membrane to the cytosol, accompanied with a reduced cell migration	SIGNOR-97942
P35222	Q96EB6	0	deacetylation	up-regulates quantity	0.505	SIRT1 deacetylates β-catenin to promote its accumulation in the nucleus and thus induces the transcription of genes that block MSC adipogenesis.	SIGNOR-256208
Q6R6M4	O14503	1	deubiquitination	up-regulates quantity by stabilization	0.2	Upon DNA damage, DEC1 is rapidly induced in an ATM/ATR-dependent manner. DEC1 induction results from protein stabilization via a mechanism that requires the USP17 ubiquitin protease. USP17 binds and deubiquitylates DEC1, markedly extending its half-life.	SIGNOR-276852
O96013	P07954	1	phosphorylation	down-regulates quantity	0.2	FH is massively phosphorylated at the Ser 46 by PAK4 in non-small cell lung cancer (NSCLC) cells, and PAK4-phosphorylated FH binds to 14-3-3, resulting in cytosolic detention of FH and prohibition of FH/CSL/p53 complex formation.	SIGNOR-266315
P11021	Q15011	0	relocalization	up-regulates quantity by stabilization	0.411	A key inhibitor of the turnover and Nt-arginylation of BiP was HERP (homocysteine-responsive ER protein), a 43-kDa ER membrane-integrated protein that is an essential component of ER-associated protein degradation.	SIGNOR-261346
Q13557	Q14654	1	phosphorylation	down-regulates	0.2	Results showed that activation of camkii triggered dynamin-dependent internalization of k(atp) channels. This process required phosphorylation of threonine at 180 and 224 and an intact (330)yskf(333) endocytosis motif of the k(atp) channel kir6.2 pore-forming subunit.	SIGNOR-200027
P42345	Q9HBH9	1	phosphorylation	down-regulates activity	0.274	MTOR phosphorylates MNK2a on Ser74. Here, we show that mTORC1, a key regulator of mRNA translation and oncogenesis, directly phosphorylates MNK2 on Ser74. This suppresses MNK2 activity and impairs binding of MNK2 to eIF4G.	SIGNOR-277516
O00273	P42574	0	cleavage	up-regulates activity	0.755	DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. We have identified and purified from HeLa cytosol a protein that induces DNA fragmentation in coincubated nuclei after it is activated by caspase-3.	SIGNOR-47416
P10586	P07949	1	dephosphorylation	down-regulates	0.426	Lar expression significantly reduced tyrosine-1062 phosphorylation in ret-men2a but not in ret-men2b	SIGNOR-85170
Q16665	P13674	1	transcriptional regulation	up-regulates quantity by expression	0.314	Hypoxia upregulates P4HA1 expression in PDAC PDOs through HIF1α. Our results show that the treatment of PDO4 and PDO11 cells with 10 μmol/L of PX-478 for 24 hours reduced the levels of P4HA1 in hypoxia (Fig. 2F), suggesting P4HA1 expression in hypoxia is regulated by HIF1α expression.	SIGNOR-279840
P17252	P29972	1	phosphorylation	up-regulates	0.2	Activation of protein kinase c (pkc) by 1-oleoyl-2-acetyl-sn-glycerol (oag) induced a marked increase of aqp1-dependent water permeability. This regulation was abolished in mutated aqp1 channels lacking both consensus pkc phosphorylation sites thr(157) and thr(239) (termed aqp1 deltapkc).	SIGNOR-155106
P55075	Q05925	0	transcriptional regulation	down-regulates quantity by repression	0.452	Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription	SIGNOR-265776
P35869	P49841	0	phosphorylation	up-regulates activity	0.25	A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR.	SIGNOR-276664
P26651	P15172	1	post transcriptional regulation	down-regulates quantity by destabilization	0.292	The TTP binding site in the 3â€² UTR of MyoD would permit TTP-mediated mRNA decay	SIGNOR-253597
Q9Y2W1	P21127	0	phosphorylation	up-regulates activity	0.206	In addition, genetic knockout of CLK1 or chemical inhibition in mice ameliorated diet-induced obesity and insulin resistance at 22\u00b0C. Through proteomics, we uncovered thyroid hormone receptor-associated protein 3 (THRAP3) as an interacting partner of CLK1, further confirmed by co-immunoprecipitation assays.\|We further demonstrated that CLK1 phosphorylates THRAP3 at Ser243, which is required for its regulatory interaction with phosphorylated peroxisome proliferator-activated receptor gamma (PPAR\u03b3), resulting in impaired adipose tissue browning and insulin sensitivity.	SIGNOR-280209
Q13144	P41091	1	guanine nucleotide exchange factor	up-regulates activity	0.735	EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.	SIGNOR-269133
P11388	P68400	0	phosphorylation	down-regulates quantity by destabilization	0.595	This study also reports the novel finding that topoIIα may be a target of GSK3β phosphorylation. Evidence suggests that CK2 serves as a priming kinase, through phosphorylation at Ser1365, for GSK3β-mediated phosphorylation at Ser1361.	SIGNOR-276300
P61289	O96017	0	phosphorylation	up-regulates activity	0.349	REGγ interacts with DBC1 and is phosphorylated by Chk2.	SIGNOR-273611
O60674	Q06187	1	phosphorylation	up-regulates activity	0.447	Jak2 and Lyn coimmunoprecipitated with Btk and phosphorylated Btk on tyrosine (XREF_FIG C).	SIGNOR-279196
Q00987	P46531	1	ubiquitination	up-regulates	0.476	Although the interaction between notch1 and mdm2 results in ubiquitination of notch1, this does not result in degradation of notch1, but instead leads to activation of the intracellular domain of notch1.	SIGNOR-200197
O15169	Q9NTX7	0	ubiquitination	down-regulates quantity by destabilization	0.645	Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation.	SIGNOR-263335
Q6PIY7	P31749	0	phosphorylation	down-regulates activity	0.2	We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition.	SIGNOR-259405
Q5S007	P61006	1	phosphorylation	up-regulates activity	0.33	In a screen for Rab8A kinases we identify TAK1 and MST3 kinases that can efficiently phosphorylate the Switch II residue Threonine72 (Thr72) in a similar manner as LRRK2 in vitro. \|Overall our data suggests that the phosphorylation of Rab8A at Ser111 may influence Switch II-binding by regulators, thus disrupting interactions with its cognate GEF and moderately impairs its interaction with GAPs.\|The antagonistic interplay between Ser111 phosphorylation and Thr72 phosphorylation is genetically concordant with how respective mutations in PINK1 and LRRK2 cause Parkinson’s disease	SIGNOR-260267
O60260	P02788	1	ubiquitination	down-regulates activity	0.2	We propose that Parkin ubiquitylation of LTF at K649 perturbs LTF\u2019s ability to accumulate intracellular iron levels and that depletion of Parkin, or substitution of K649 on LTF, allows LTF to accumulate intracellular iron levels.\|Parkin dependent ubiquitylation of LTF occurred most often on lysines (K) 182 and 649.	SIGNOR-278641
Q7Z6Z7	O95251	1	ubiquitination	down-regulates quantity by destabilization	0.2	Moreover, we determined that Huwe1 is a novel E3 ligase for Myst2 degradation in mESCs, and Brpf3 disturbs Huwe1 mediated ubiquitination of Myst2 via interaction with Huwe1 and Myst2.	SIGNOR-278652
Q12968	P45983	0	phosphorylation	down-regulates	0.837	Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin	SIGNOR-118220
Q9C037	O75298	1	ubiquitination	down-regulates quantity	0.2	2: TRIM4 ubiquitinates and degrades the NSP2 protein.\|Mechanistic studies showed that TRIM4 ubiquitinated modified NSP2 and down-regulated NSP2 expression.	SIGNOR-278793
P35813	Q86WV6	1	dephosphorylation	down-regulates activity	0.2	Collectively, our findings suggest that the overexpression of PPM1A antagonizes the STING- and TBK1-induced type I interferon signaling pathway.\|First, PPM1A directly dephosphorylated STING, likely via its S358 site (Figs.\|Moreover, our study demonstrates that while TBK1 enhances STING aggregation in a kinase activity-dependent manner, PPM1A suppresses STING aggregation by dephosphorylating both STING and TBK1.	SIGNOR-276958
Q5XPI4	P45973	1	polyubiquitination	down-regulates quantity by destabilization	0.2	In the present study, we report that HP1α and β undergo proteasomal degradation in lamin A/C knock-down cells and show by ectopic expression, RNAi and binding studies that the RING finger ubiquitin ligase RNF123 is directly involved in HP1 degradation.	SIGNOR-272035
P04637	Q14694	0	deubiquitination	up-regulates quantity by stabilization	0.662	Since USP10 is known as a deubiquitinating protease of p53 (Yuan et al., 2010), inhibition of USP10 by spautin-1 may promote the degradation of p53.	SIGNOR-260297
O96017	P10636	1	phosphorylation	down-regulates	0.2	Tau pseudophosphorylation at specific sites such as s262, s293, s324 and s356 was reported to induce tau conformational change and attenuate tau binding to microtubules (fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process	SIGNOR-171026
P67775	Q04206	1	dephosphorylation	down-regulates	0.483	Rela was dephosphorylated by a purified pp2a core enzyme, a heterodimer formed by the catalytic subunit of pp2a (pp2ac) and pr65, in a concentration-dependent manner.These data suggest that the constitutive activation of rela in melanoma cells could be due, at least in part, to the deficiency of pp2a, which exhibits decreased dephosphorylation of nf-kappa b/rela.	SIGNOR-110959
P52926	P06493	0	phosphorylation	down-regulates	0.374	Architecture of high mobility group protein i-c dna complex and its perturbation upon phosphorylation by cdc2 kinase. Phosphorylation by cdc2 reduces binding strength of the mammalian and insect hmgi proteins to dna. After phosphorylation of the protein at ser-43 and ser-58 by cdc2 kinase multiple contacts of dbds, especially with the bases, are impaired and the protein binds to dna in a different way, extending the contacts to the sugar-phosphate backbone.	SIGNOR-74098
O15264	Q12888	1	phosphorylation	down-regulates activity	0.2	Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.\|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks \|phosphorylation of T1609 is likely to be mediated by p38 MAPK	SIGNOR-264449
P28482	O60674	1	phosphorylation	down-regulates	0.513	We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner	SIGNOR-236331
Q13882	Q12929	1	phosphorylation	up-regulates activity	0.357	Eps8 which was identified by this method is phosphorylated by Myr-PTK6 in HEK293 cells. Mouse Eps8 expressed in HEK293 cells is phosphorylated by Myr-PTK6 at residues Tyr497, Tyr524, and Tyr534. These results indicate that plasma-membrane-associated PTK6 phosphorylates Eps8, which promotes cell proliferation, adhesion, and migration and, thus, tumorigenesis.	SIGNOR-263191
P06239	P22681	0	polyubiquitination	down-regulates quantity by destabilization	0.711	Coexpression in 293T cells demonstrated that Lck kinase activity and Cbl ubiquitin ligase activity were essential for Lck ubiquitination and negative regulation of Lck-dependent serum response element-luciferase reporter activity. The Lck SH3 domain was pivotal for Cbl-Lck association and Cbl-mediated Lck degradation, with a smaller role for interactions mediated by the Cbl tyrosine kinase-binding domain.	SIGNOR-272614
Q15746	P00519	0	phosphorylation	up-regulates	0.3	Nonmuscle myosin light chain kinase (nmmlck), a multi-functional cytoskeletal protein critical to vascular homeostasis, is highly regulated by tyrosine phosphorylation. We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity	SIGNOR-167989
P20336	P53611	0	lipidation	up-regulates activity	0.656	Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional	SIGNOR-265575
P17612	Q9Y6D6	1	phosphorylation	up-regulates activity	0.2	Within 20 min after addition of 8-Br-cAMP, BIG1 accumulated in nuclei, and this effect was blocked by protein kinase A (PKA) inhibitors H-89 and PKI, suggesting a dependence on PKA-catalyzed phosphorylation. \|Mutant BIG1 (S883A) in which Ala replaced Ser-883, a putative PKA phosphorylation site, did not move to the nucleus with cAMP addition, whereas replacement with Asp (S883D) resulted in nuclear accumulation of BIG1 without or with cAMP exposure, consistent with the mechanistic importance of a negative charge at that site	SIGNOR-272146
P35968	P48730	0	phosphorylation	down-regulates activity	0.328	CKIdelta phosphorylates VEGFR2 at both DSG and DDTD phosphodegrons to promote its interaction with beta-TRCP1.\|In a reciprocal set of experiments, we found that overexpression of CKIdelta markedly decreased the half-life of VEGFR2 (XREF_FIG).	SIGNOR-280235
P27216	P46934	1	relocalization	up-regulates quantity	0.344	Annexin XIII has two known isoforms, a and b, that are apically localized, although XIIIa is also found in the basolateral compartment. In vitro binding and coprecipitation experiments showed that the Nedd4-C2 domain interacts with both annexin XIIIa and b in the presence of Ca2+, and the interaction is direct and optimal at 1 μM Ca2+.These results suggest that the apical membrane localization of Nedd4 is mediated by an association of its C2 domain with the apically targeted annexin XIIIb.	SIGNOR-272571
Q99683	Q5SGD2	0	dephosphorylation	down-regulates	0.318	Exogenous pp2cepsilon associated with exogenous ask1 in hek-293 cells under non-stressed conditions, inactivating ask1 by decreasing thr845 phosphorylation	SIGNOR-154554
P49137	Q16539	0	phosphorylation	up-regulates activity	0.769	Here we show that in vitro rk phosphorylates human gst-mapkap kinase-2 at thr25 in the proline-rich n-terminal region thr222 and ser272 in the catalytic domain and thr334 in the c-terminal domain. Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation	SIGNOR-44351
O94953	P04637	0	transcriptional regulation	up-regulates quantity by expression	0.281	KDM4B/JMJD2B is a p53 target gene that modulates the amplitude of p53 response after DNA damage. p53 directly regulates JMJD2B gene expression by binding to a canonical p53-consensus motif in the JMJD2B promoter.	SIGNOR-263729
P35813	Q16539	1	dephosphorylation	down-regulates activity	0.408	Moreover, when expressed in mammalian cells, pp2ca inhibited the activation of the p38 and jnk cascades induced by environmental stresses. Both in vivo and in vitro observations indicated that pp2ca dephosphorylated and inactivated mapkks (mkk6 and sek1) and a mapk (p38) in the stress-responsive mapk cascades. Furthermore, a direct interaction of pp2ca and p38 was demonstrated by a co-immunoprecipitation assay	SIGNOR-59618
Q13153	P27361	0	phosphorylation	down-regulates	0.337	Activated erk can phosphorylate t292 in the prs, and this blocks the ability of pak to phosphorylate s298 and of rac-pak signaling to enhance mek1-erk complex formation.	SIGNOR-123074
Q14653	Q12899	0	polyubiquitination	down-regulates quantity by destabilization	0.672	TRIM26 bound to IRF3 and promoted its K48-linked polyubiquitination and degradation in nucleus.	SIGNOR-272440
P17302	P05129	0	phosphorylation	down-regulates activity	0.568	Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.\|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication.	SIGNOR-249050
P46531	Q8NBL1	0	glycosylation	up-regulates	0.606	O-glucosylation of epidermal growth factor-like (egf) repeats in the extracellular domain of notch is essential for notch function. A udp-glucose:protein o-glucosyltransferase (poglut/rumi) transfers o-glucose to serine within the o-glucose consensus.	SIGNOR-198713
P12931	Q13642	1	phosphorylation	up-regulates activity	0.26	However, overexpression of Src promoted most of the Flag-FHL1-WT to translocate to the nucleus, whereas the Flag-FHL1-Y149-272F mutant (phosphorylation deficient mutant) remained in the cytoplasm (XREF_FIG).\|We found that Src phosphorylates FHL1 at Y149 and Y272, demonstrating that FHL1 is a bona fide novel substrate of Src.	SIGNOR-278213
Q14191	P78527	0	phosphorylation	up-regulates	0.641	Here, we identify ser-440 and -467 in wrn as major phosphorylation sites mediated by dna-pk our findings indicate that phosphorylation of ser-440 and -467 in wrn are important for relocalization of wrn to nucleoli, and that it is required for efficient dsb repair.	SIGNOR-203737
P28482	P50548	1	phosphorylation	up-regulates	0.596	The experiments presented here indicate that erf is regulated during nuclear import and/or export and that this process depends on its phosphorylation by erks our analysis indicates that in addition to t526 (position 7), s161 (position 2), s246 (position 3), and s251 (position 4) are also phosphorylated in vitro by erk2 and in vivo after mitogenic stimulation (fig. 3a).	SIGNOR-67524
O96017	Q13972	1	phosphorylation	down-regulates	0.405	During interphase, cdc25 is inhibited by ser287 phosphorylation (xenopus cdc25;ser 216 in human cdc25c) and this inhibitory phosphorylation is maintained by dna-responsive checkpoints / s287 is targeted by many kinases, including chk1, chk2, ctak-1, pka, p38 and mapkap kinase-2 suggesting that phosphorylation of this site may integrate multiple signaling inputs.	SIGNOR-150843
P01189-PRO_0000024969	P29120	0	cleavage	up-regulates quantity	0.2	POMC is post-translationally cleaved by prohormone convertase enzymes 1 and 2 (PC1, PC2) into ACTH, an N-terminal glycopeptide	SIGNOR-268724
P15172	Q12857	0	transcriptional regulation	up-regulates quantity by expression	0.246	NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma\|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog,	SIGNOR-263982
Q9ULT6	O60353	1	ubiquitination	down-regulates quantity	0.614	Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6.	SIGNOR-260114
Q13541	P49841	0	phosphorylation	down-regulates activity	0.364	We found that gsk-3Beta phosphorylates and inactivates 4e-bp1, thereby increasing eif4e-dependent protein synthesis. upon stimulation, 4e-bp1 is phosphorylated on several threonine and serine residues, including thr-37/46 (36). This results in dissolution of the complex, freeing eif4e to bind with mrna cap to promote translation initiation.	SIGNOR-236026
Q9ULU4	P30542	1	transcriptional regulation	up-regulates quantity by expression	0.2	We also confirmed transcriptional coactivator functions of ZMYND8 in ERα-driven reporter assays and on endogenous E2-dependent genes (Figure 5F,G). siRNA knockdown of ZMYND8 showed markedly decreased transcription at the presumptive ERα/Z3 target genes ADORA1 and NAV2, while the classical ERα targets pS2/TFF1 and GREB1 appear to be less affected (Figure 5G), suggesting likely gene-specificity of ZMYND8.	SIGNOR-266208
Q92831	Q16695	1	acetylation	down-regulates activity	0.2	The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.	SIGNOR-269621
Q8TCQ1	P13762	1	polyubiquitination	down-regulates quantity by destabilization	0.2	Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination.	SIGNOR-271409
P35813	Q14164	1	dephosphorylation	down-regulates activity	0.279	PPM1A directly dephosphorylates both MAVS and TBK1 and IKKepsilon.\|In a similar in vitro phosphatase assay, incubation of PPM1A also eliminated TBK1 and IKKepsilon phosphorylation at Ser 172 residue, evidenced by phospho-S172 immunoblotting (XREF_FIG, F and G).\|These observations suggest that PPM1A may block kinase activities of TBK1 and IKKepsilon.	SIGNOR-277072
Q14940	P32121	0	relocalization	down-regulates activity	0.397	Internalization of the Na(+)/H(+) exchanger NHE5 into recycling endosomes is enhanced by the endocytic adaptor proteins beta-arrestin1 and -2, best known for their preferential recognition of ligand-activated G protein-coupled receptors (GPCRs)	SIGNOR-275506
P45974	Q08050	1	deubiquitination	up-regulates quantity by stabilization	0.351	Wnt signaling activation inhibits FoxM1 phosphorylation by GSK3-Axin complex and leads to interaction between FoxM1 and deubiquitinating enzyme USP5, thereby deubiquitination and stabilization of FoxM1.	SIGNOR-277210
P09211	Q05513	0	phosphorylation	up-regulates activity	0.2	Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently	SIGNOR-276017
Q9Y297	Q13315	0	phosphorylation	up-regulates quantity by stabilization	0.299	ATM phosphorylates and stabilizes β-TrCP1 upon DNA damage.	SIGNOR-277549
Q15208	P38936	1	phosphorylation	down-regulates quantity by destabilization	0.2	More importantly, with the direct regulation of p21 stability by phosphorylation on Ser 146, we define here the first downstream signaling mechanisms by which NDR kinases can control G1/S progression.\|NDR kinases regulate p21 stability by phosphorylation of S146 on p21. \|	SIGNOR-272961
P05107	O60674	0	phosphorylation	up-regulates activity	0.265	PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role.	SIGNOR-254738
P07948	P53396	1	phosphorylation	up-regulates activity	0.2	We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells.	SIGNOR-274105
Q15797	P36894	0	phosphorylation	up-regulates activity	0.732	Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression.	SIGNOR-255263

P10451

Q13950

0

transcriptional regulation

up-regulates quantity

0.488

Ets-1 and Runx2 are critical transcriptional regulators of OPN expression in CT26 colorectal cancer cells. Suppression of these transcription factors results in significant down-regulation of the OPN metastasis protein.

SIGNOR-245336

P43403

P06241

0

phosphorylation

up-regulates activity

0.574

Subsequently, Lck and Fyn phosphorylate and activate the Syk family kinase ZAP-70 when it is recruited to the phosphorylated ITAM motifs xref .

SIGNOR-279043

P52292

Q09472

0

acetylation

up-regulates

0.357

Ampk triggered the acetylation of importin alpha1 on lys(22), a process dependent on the acetylase activity of p300

SIGNOR-128625

O14733

Q13233

0

phosphorylation

up-regulates

0.723

Here we show that jnkk2, a novel member of the map kinase kinase family, was phosphorylated and activated by mekk1

SIGNOR-51207

Q9UKX5

Q02447

0

null

up-regulates quantity by expression

0.2

We speculate that the "mesenchymal signature" of alpha11 integrin gene expression is controlled by the activity of Sp1/Sp3, fibroblast-specific combinations of Ets family members and yet unidentified enhancer-binding transcription factors.

SIGNOR-253351

O14770

P42771

1

transcriptional regulation

up-regulates quantity by expression

0.2

We show that the Pbx1 and Meis2 homeodomain proteins interact with Klf4 and can be recruited to DNA elements comprising a Klf4 site or G C box, with adjacent Meis and Pbx sites. Meis2d and Pbx1a activate expression of p15(Ink4a) and E-cadherin, dependent on the Meis2d transcriptional activation domain. We suggest a model in which genes with Klf4 sites can be cooperatively activated by Meis2/Pbx1 and Klf4, dependent primarily on recruitment by Klf4.

SIGNOR-267240

P19525

Q9NYA1

1

phosphorylation

up-regulates activity

0.2

This suggests that PKR is critical in the phosphorylation of SPHK1 at Ser225.|We confirmed that phosphorylated PKR activates SPHK1 kinase activity, but it remained necessary to determine whether there has mutual correlation or any reciprocal effect between these two kinases in stressed cells.

SIGNOR-278514

Q5S007

P61026

1

phosphorylation

down-regulates activity

0.33

To investigate whether the phosphorylation of Rab10 by LRRK2 is direct, we performed an in vitro kinase assay using recombinant components. Notably, we found that both wt and LRRK2-G2019S, but neither kinase inactive D1994A mutant nor small molecule-inhibited LRRK2, efficiently phosphorylated Rab10, proving a direct kinase-substrate relationship (Figure 2C). Furthermore, incubation of Rab10 with LRRK2 followed by tryptic digestion and MS analysis unambiguously identified T73 as the major phosphorylation site (Figure 2—figure supplement 1B)|In pathogenic conditions, in which LRRK2 is hyperactive, RabGTPases have strongly diminished affinities for GDIs.

SIGNOR-261277

P53778

Q13424

1

phosphorylation

up-regulates

0.668

Sapk3 phosphorylates alpha1-syntrophin at serine residues 193 and 201 in vitro and phosphorylation is dependent on binding to the pdz domain of alpha1-syntrophin. The finding that sapk3 co-localizes with _1-syntrophin in skeletal muscle, that it binds to the pdz domain of _1-syntrophin, and that phosphorylation of _1-syntrophin depends on this interaction identifies a novel mechanism for targeting a protein kinase to its substrates.

SIGNOR-67061

P50613

Q9NYV4

1

phosphorylation

up-regulates activity

0.51

Although Cdk12/CycK kinase complex lacking T-loop phosphorylation showed some basal activity towards a CTD substrate prephosphorylated at position Ser7, its activity was significantly increased upon coexpression with the CAK from S. cerevisiae (Supplementary Fig. 9a). Mutation of T893 to E to mimic phosphorylation showed no effect on basal kinase activity. Quantitative phosphorylation of a single residue occurred upon coexpression with Cak1, as determined by ESI mass spectrometry (Supplementary Fig. 9b).

SIGNOR-275509

P10644

P24941

0

phosphorylation

up-regulates

0.343

In this context, we have identified rialpha as a novel substrate for the g(1)/s-cyclin-dependent kinase, cdk2/cyclin e, and found that rialpha is specifically phosphorylated at the serine residue.

SIGNOR-145577

B2RTY4

P61586

1

gtpase-activating protein

down-regulates activity

0.565

We therefore developed a screening-compatible live-cell imaging assay, using FRET-based biosensors for the prototype GTPases RHOA, RAC1 and CDC4215,19,20 (Extended Data Fig. 2 and Supplementary Note 1)|We found catalytic activities for 45/75 RhoGEFs and 48/63 RhoGAPs| Our data thus not only reveal extensive promiscuity among regulators, but also that the inactivating RhoGAPs are less selective than the activating RhoGEFs (p-value=0.02)(Supplementary Table 2).

SIGNOR-260508

P00540

Q02750

1

phosphorylation

up-regulates activity

0.485

Our data indicate that Mos activated MEK1 in vitro as well as in vivo by phosphorylating Ser 222.

SIGNOR-260920

Q96J02

Q7Z434

1

ubiquitination

down-regulates quantity by destabilization

0.646

These data collectively indicate that AIP4 is the E3 ligase for MAVS.|We generated single substitutions (K362A, K371A or K420A) and combined point substitutions of MAVS and tested their degradation. K371A or K420A MAVS showed partial resistance to PCBP2-induced degradation (data not shown), whereas MAVS with the combined substitutions K371A and K420A (KK-AA) completely withstood the degradation

SIGNOR-260362

Q96DX5

P12277

1

polyubiquitination

down-regulates quantity by destabilization

0.683

We demonstrate that creatine kinase B (CKB) interacts with Asb-9 in a specific, SOCS box-independent manner. This interaction increases the polyubiquitylation of CKB and decreases total CKB levels within the cell. The targeting of CKB for degradation by Asb-9 was primarily SOCS box-dependent and suggests that Asb-9 acts as a specific ubiquitin ligase regulating levels of this evolutionarily conserved enzyme.

SIGNOR-271623

Q9UKX2

Q14814

0

transcriptional regulation

up-regulates quantity by expression

0.327

Myocyte enhancer factor-2 and serum response factor binding elements regulate fast Myosin heavy chain transcription in vivo. We show that the upstream promoter region of the gene most abundantly expressed in mouse skeletal muscles, IIb MyHC, retains binding activity and transcriptional activation for three positive transcription factors, the serum response factor, Oct-1, and myocyte enhancer factor-2, whereas the other two genes (IIa and IId/x) have nucleotide substitutions in these sites that reduce binding and transcriptional activation

SIGNOR-238712

O14757

P12830

1

phosphorylation

down-regulates activity

0.301

Phosphorylation of Cdh1 by Chk1 promotes recognition of Cdh1 by SCF betaTRCP1.|These data suggest that Chk1 negatively regulates APC/C Cdh1 activity by both promoting Cdh1 destruction and by destabilizing its association with the APC/C.

SIGNOR-278396

P36897

P29353

1

phosphorylation

up-regulates

0.548

We now report that upon TGF-_ stimulation, T_RI phosphorylates ShcA on serine and, to a lesser degree, on tyrosine to activate Erk MAP kinases.

SIGNOR-227503

P29350

P32927

1

dephosphorylation

down-regulates

0.522

However, inhibition of shp2 binding to betac, did not prevent tyrosine phosphorylation of shp2. Interestingly, this same phosphopeptide served as a substrate for the tyrosine phosphatase activity of both shp1 and shp2.

SIGNOR-114597

O00743

Q8N884

1

dephosphorylation

down-regulates activity

0.2

In this study, we found that PPP6C suppressed phosphorylation of human cGAS (hcGAS) at S435 or mouse cGAS (mcGAS) at S420 in its substrate-binding pocket, thus preventing its binding to GTP and inhibiting the synthesis of cGAMP.|These data suggest that PPP6C inhibits cGAS activity.

SIGNOR-276990

P12931

O15524

1

phosphorylation

down-regulates activity

0.45

SOCS1 is phosphorylated on Y80 by SRC family kinase members SRC and YES1.

SIGNOR-276857

P46937

P31749

0

phosphorylation

down-regulates

0.593

One protein that associates with 14-3-3 in an akt-dependent manner is shown here to be the yes-associated protein (yap), which is phosphorylated by akt at serine 127, leading to binding to 14-3-3. Akt promotes yap localization to the cytoplasm, resulting in loss from the nucleus where it functions as a coactivator of transcription factors including p73.

SIGNOR-252593

P31645

P12931

0

phosphorylation

up-regulates quantity by stabilization

0.258

We found that 1) SERT exists in a tyrosine-phosphorylated form, 2) inhibition of tyrosine kinase(s) reduces SERT expression levels by facilitating SERT protein degradation, 3) Src-kinase activity up-regulates SERT protein expression with a concomitant increase in 5-HT uptake and tyrosine phosphorylation, and 4) mutation of Tyr47 or Tyr142 abolishes src-induced increases in transport function and phosphorylation of SERT.

SIGNOR-276386

P50549

Q15418

0

phosphorylation

up-regulates activity

0.35

Here we describe that the 90-kDa ribosomal S6 kinase 1 (RSK1), a protein kinase downstream of the extracellular signal-regulated kinase (ERK) subclass of MAPKs, binds to ER81, phosphorylates it, and enhances ER81-dependent transcription. Two in vivo RSK1 phosphorylation sites within ER81, Ser(191) and Ser(216), were identified, whose mutation to alanine reduces ER81 activity upon ERK-MAPK stimulation.

SIGNOR-249163

O95398

P62834

1

guanine nucleotide exchange factor

up-regulates activity

0.71

Epac1 (cAMP-GEFI) and Epac2 (cAMP-GEFII) are closely related guanine nucleotide exchange factors (GEFs) for the small GTPase Rap1, which are directly regulated by cAMP. Here we show that both GEFs efficiently activate Rap2 as well.

SIGNOR-263956

O60936

P68400

0

phosphorylation

up-regulates activity

0.324

Phosphorylation of ARC at T149 Is Required for Its Antiapoptotic Effect. Here we report that the function of ARC is regulated by protein kinase CK2. ARC at threonine 149 is phosphorylated by CK2. This phosphorylation targets ARC to mitochondria. ARC is able to bind to caspase-8 only when it is localized to mitochondria but not to the cytoplasm.

SIGNOR-262837

P31749

Q9BRS8

1

phosphorylation

up-regulates activity

0.353

Akt dependent phosphorylation of LARP6. We provide the first description that LARP6 is phosphorylated at multiple sites and that phosphorylation of S451 is critical to activate the protein in type I collagen biosynthesis.

SIGNOR-277213

P00519

Q99638

1

phosphorylation

up-regulates activity

0.477

The SH3 domain of c-Abl interacts directly with the C-terminal region of Rad9. c-Abl phosphorylates the Rad9 Bcl-2 homology 3 domain (Tyr-28) in vitro and in cells exposed to DNA-damaging agents. | c-Abl-mediated phosphorylation of Rad9 induces binding of Rad9 to Bcl-xL |these findings indicate that Rad9 is regulated by a c-Abl-dependent mechanism in the apoptotic response to genotoxic stress.

SIGNOR-260843

Q13443

P50281

0

cleavage

down-regulates quantity by destabilization

0.341

Here we show that MT1-MMP forms a complex with FGFR2 and ADAM9 in osteoblasts and proteolytically inactivates ADAM9|Western blotting using antibodies against ectodomain of ADAM9 detected a fragment (around 26 kDa) of ADAM9 in the conditioned culture medium from cells cotransfected with wild-type MT1-MMP, but not in that with catalytic activity-dead MT1-MMP (Figure 6A, top).

SIGNOR-260301

P04637

P06493

0

phosphorylation

up-regulates activity

0.579

The N-terminus of E2F1 can interact directly with a region towards the C-terminus of p53, resulting in increased nuclear retention of p53 and p53-mediated transcription and apoptosis. This is inhibited by competition between p53 and cyclin A at the binding site within E2F19,10. The interaction between p53 and E2F1 is enhanced by phosphorylation of p53 on Ser315, a residue within the E2F1 binding region that is phosphorylated by cell cycle kinases such as cdk1, cdk2, cdk9 and Aurora kinase A

SIGNOR-167779

P05771

Q14847

1

phosphorylation

down-regulates activity

0.2

Actin binding of human lim and sh3 protein is regulated by cgmp- and camp-dependent protein kinase phosphorylation on serine 146. Phosphorylation of lasp at ser-146 leads to a redistribution of the actin-bound protein from the tips of the cell membrane to the cytosol, accompanied with a reduced cell migration

SIGNOR-97942

P35222

Q96EB6

0

deacetylation

up-regulates quantity

0.505

SIRT1 deacetylates β-catenin to promote its accumulation in the nucleus and thus induces the transcription of genes that block MSC adipogenesis.

SIGNOR-256208

Q6R6M4

O14503

1

deubiquitination

up-regulates quantity by stabilization

0.2

Upon DNA damage, DEC1 is rapidly induced in an ATM/ATR-dependent manner. DEC1 induction results from protein stabilization via a mechanism that requires the USP17 ubiquitin protease. USP17 binds and deubiquitylates DEC1, markedly extending its half-life.

SIGNOR-276852

O96013

P07954

1

phosphorylation

down-regulates quantity

0.2

FH is massively phosphorylated at the Ser 46 by PAK4 in non-small cell lung cancer (NSCLC) cells, and PAK4-phosphorylated FH binds to 14-3-3, resulting in cytosolic detention of FH and prohibition of FH/CSL/p53 complex formation.

SIGNOR-266315

P11021

Q15011

0

relocalization

up-regulates quantity by stabilization

0.411

A key inhibitor of the turnover and Nt-arginylation of BiP was HERP (homocysteine-responsive ER protein), a 43-kDa ER membrane-integrated protein that is an essential component of ER-associated protein degradation.

SIGNOR-261346

Q13557

Q14654

1

phosphorylation

down-regulates

0.2

Results showed that activation of camkii triggered dynamin-dependent internalization of k(atp) channels. This process required phosphorylation of threonine at 180 and 224 and an intact (330)yskf(333) endocytosis motif of the k(atp) channel kir6.2 pore-forming subunit.

SIGNOR-200027

P42345

Q9HBH9

1

phosphorylation

down-regulates activity

0.274

MTOR phosphorylates MNK2a on Ser74. Here, we show that mTORC1, a key regulator of mRNA translation and oncogenesis, directly phosphorylates MNK2 on Ser74. This suppresses MNK2 activity and impairs binding of MNK2 to eIF4G.

SIGNOR-277516

O00273

P42574

0

cleavage

up-regulates activity

0.755

DFF, a heterodimeric protein that functions downstream of caspase-3 to trigger DNA fragmentation during apoptosis. We have identified and purified from HeLa cytosol a protein that induces DNA fragmentation in coincubated nuclei after it is activated by caspase-3.

SIGNOR-47416

P10586

P07949

1

dephosphorylation

down-regulates

0.426

Lar expression significantly reduced tyrosine-1062 phosphorylation in ret-men2a but not in ret-men2b

SIGNOR-85170

Q16665

P13674

1

transcriptional regulation

up-regulates quantity by expression

0.314

Hypoxia upregulates P4HA1 expression in PDAC PDOs through HIF1α. Our results show that the treatment of PDO4 and PDO11 cells with 10 μmol/L of PX-478 for 24 hours reduced the levels of P4HA1 in hypoxia (Fig. 2F), suggesting P4HA1 expression in hypoxia is regulated by HIF1α expression.

SIGNOR-279840

P17252

P29972

1

phosphorylation

up-regulates

0.2

Activation of protein kinase c (pkc) by 1-oleoyl-2-acetyl-sn-glycerol (oag) induced a marked increase of aqp1-dependent water permeability. This regulation was abolished in mutated aqp1 channels lacking both consensus pkc phosphorylation sites thr(157) and thr(239) (termed aqp1 deltapkc).

SIGNOR-155106

P55075

Q05925

0

transcriptional regulation

down-regulates quantity by repression

0.452

Our results in ES cells suggest that Engrailed inhibits Fgf8 expression in the absence of Pbx1. We identified single Engrailed- and Pbx-binding sites in the Fgf8 intron that inhibit expression of Fgf8 in mouse ES cells, but that together can allow full Fgf8 expression. Our data support the model that Engrailed heterodimerized with Pbx might activate transcription, while Engrailed or Pbx proteins alone might repress transcription

SIGNOR-265776

P35869

P49841

0

phosphorylation

up-regulates activity

0.25

A proposed model of GSK3β role on AHR function and degradation. AHR is phosphorylated by GSK3β in a p23-dependent manner in HeLa cells. This phosphorylation is required for optimal activation of the ligand-dependent AHR target gene transcription. After phosphorylation, AHR is K63-ubiquitinated and is targeted for the LC3-mediated selective autophagy. When the p23 content is compromised in HeLa cells, AHR is more prone to degradation via autophagy, bypassing the GSK3β phosphorylation of AHR.

SIGNOR-276664

P26651

P15172

1

post transcriptional regulation

down-regulates quantity by destabilization

0.292

The TTP binding site in the 3â€² UTR of MyoD would permit TTP-mediated mRNA decay

SIGNOR-253597

Q9Y2W1

P21127

0

phosphorylation

up-regulates activity

0.206

In addition, genetic knockout of CLK1 or chemical inhibition in mice ameliorated diet-induced obesity and insulin resistance at 22\u00b0C. Through proteomics, we uncovered thyroid hormone receptor-associated protein 3 (THRAP3) as an interacting partner of CLK1, further confirmed by co-immunoprecipitation assays.|We further demonstrated that CLK1 phosphorylates THRAP3 at Ser243, which is required for its regulatory interaction with phosphorylated peroxisome proliferator-activated receptor gamma (PPAR\u03b3), resulting in impaired adipose tissue browning and insulin sensitivity.

SIGNOR-280209

Q13144

P41091

1

guanine nucleotide exchange factor

up-regulates activity

0.735

EIF2B converts the protein synthesis initiation factor 2 (eIF2) from an inactive GDP-bound form to an active eIF2-GTP complex owing to its guanine nucleotide exchange factor (GEF) activity.

SIGNOR-269133

P11388

P68400

0

phosphorylation

down-regulates quantity by destabilization

0.595

This study also reports the novel finding that topoIIα may be a target of GSK3β phosphorylation. Evidence suggests that CK2 serves as a priming kinase, through phosphorylation at Ser1365, for GSK3β-mediated phosphorylation at Ser1361.

SIGNOR-276300

P61289

O96017

0

phosphorylation

up-regulates activity

0.349

REGγ interacts with DBC1 and is phosphorylated by Chk2.

SIGNOR-273611

O60674

Q06187

1

phosphorylation

up-regulates activity

0.447

Jak2 and Lyn coimmunoprecipitated with Btk and phosphorylated Btk on tyrosine (XREF_FIG C).

SIGNOR-279196

Q00987

P46531

1

ubiquitination

up-regulates

0.476

Although the interaction between notch1 and mdm2 results in ubiquitination of notch1, this does not result in degradation of notch1, but instead leads to activation of the intracellular domain of notch1.

SIGNOR-200197

O15169

Q9NTX7

0

ubiquitination

down-regulates quantity by destabilization

0.645

Here, we identify RNF146, a RING-domain E3 ubiquitin ligase, as a positive regulator of Wnt signalling. RNF146 promotes Wnt signalling by mediating tankyrase-dependent degradation of axin. Mechanistically, RNF146 directly interacts with poly(ADP-ribose) through its WWE domain, and promotes degradation of PARsylated proteins. Using proteomics approaches, we have identified BLZF1 and CASC3 as further substrates targeted by tankyrase and RNF146 for degradation.

SIGNOR-263335

Q6PIY7

P31749

0

phosphorylation

down-regulates activity

0.2

We found that Gld2 activity is regulated by site-specific phosphorylation in its disordered N-terminal domain. We identified two phosphorylation sites (S62, S110) where phosphomimetic substitutions increased Gld2 activity and one site (S116) that markedly reduced activity. Using mass spectrometry, we confirmed that HEK 293 cells readily phosphorylate the N-terminus of Gld2. We identified protein kinase A (PKA) and protein kinase B (Akt1) as the kinases that site-specifically phosphorylate Gld2 at S116, abolishing Gld2-mediated nucleotide addition.

SIGNOR-259405

Q5S007

P61006

1

phosphorylation

up-regulates activity

0.33

In a screen for Rab8A kinases we identify TAK1 and MST3 kinases that can efficiently phosphorylate the Switch II residue Threonine72 (Thr72) in a similar manner as LRRK2 in vitro. |Overall our data suggests that the phosphorylation of Rab8A at Ser111 may influence Switch II-binding by regulators, thus disrupting interactions with its cognate GEF and moderately impairs its interaction with GAPs.|The antagonistic interplay between Ser111 phosphorylation and Thr72 phosphorylation is genetically concordant with how respective mutations in PINK1 and LRRK2 cause Parkinson’s disease

SIGNOR-260267

O60260

P02788

1

ubiquitination

down-regulates activity

0.2

We propose that Parkin ubiquitylation of LTF at K649 perturbs LTF\u2019s ability to accumulate intracellular iron levels and that depletion of Parkin, or substitution of K649 on LTF, allows LTF to accumulate intracellular iron levels.|Parkin dependent ubiquitylation of LTF occurred most often on lysines (K) 182 and 649.

SIGNOR-278641

Q7Z6Z7

O95251

1

ubiquitination

down-regulates quantity by destabilization

0.2

Moreover, we determined that Huwe1 is a novel E3 ligase for Myst2 degradation in mESCs, and Brpf3 disturbs Huwe1 mediated ubiquitination of Myst2 via interaction with Huwe1 and Myst2.

SIGNOR-278652

Q12968

P45983

0

phosphorylation

down-regulates

0.837

Jnks directly phosphorylate nuclear factor of activated t-cell (nfat) transcription factors, thus antagonizing the effects of calcium-regulated signaling through the protein phosphatase calcineurin

SIGNOR-118220

Q9C037

O75298

1

ubiquitination

down-regulates quantity

0.2

2: TRIM4 ubiquitinates and degrades the NSP2 protein.|Mechanistic studies showed that TRIM4 ubiquitinated modified NSP2 and down-regulated NSP2 expression.

SIGNOR-278793

P35813

Q86WV6

1

dephosphorylation

down-regulates activity

0.2

Collectively, our findings suggest that the overexpression of PPM1A antagonizes the STING- and TBK1-induced type I interferon signaling pathway.|First, PPM1A directly dephosphorylated STING, likely via its S358 site (Figs.|Moreover, our study demonstrates that while TBK1 enhances STING aggregation in a kinase activity-dependent manner, PPM1A suppresses STING aggregation by dephosphorylating both STING and TBK1.

SIGNOR-276958

Q5XPI4

P45973

1

polyubiquitination

down-regulates quantity by destabilization

0.2

In the present study, we report that HP1α and β undergo proteasomal degradation in lamin A/C knock-down cells and show by ectopic expression, RNAi and binding studies that the RING finger ubiquitin ligase RNF123 is directly involved in HP1 degradation.

SIGNOR-272035

P04637

Q14694

0

deubiquitination

up-regulates quantity by stabilization

0.662

Since USP10 is known as a deubiquitinating protease of p53 (Yuan et al., 2010), inhibition of USP10 by spautin-1 may promote the degradation of p53.

SIGNOR-260297

O96017

P10636

1

phosphorylation

down-regulates

0.2

Tau pseudophosphorylation at specific sites such as s262, s293, s324 and s356 was reported to induce tau conformational change and attenuate tau binding to microtubules (fischer et al., 2009). Then, newly soluble tau proteins are targeted by post-translational modifications that directly or indirectly alter tau conformation, promoting tau dimerization in an anti-parallel manner. Stable tau dimers form tau oligomers, which continue in the aggregation process

SIGNOR-171026

P67775

Q04206

1

dephosphorylation

down-regulates

0.483

Rela was dephosphorylated by a purified pp2a core enzyme, a heterodimer formed by the catalytic subunit of pp2a (pp2ac) and pr65, in a concentration-dependent manner.These data suggest that the constitutive activation of rela in melanoma cells could be due, at least in part, to the deficiency of pp2a, which exhibits decreased dephosphorylation of nf-kappa b/rela.

SIGNOR-110959

P52926

P06493

0

phosphorylation

down-regulates

0.374

Architecture of high mobility group protein i-c dna complex and its perturbation upon phosphorylation by cdc2 kinase. Phosphorylation by cdc2 reduces binding strength of the mammalian and insect hmgi proteins to dna. After phosphorylation of the protein at ser-43 and ser-58 by cdc2 kinase multiple contacts of dbds, especially with the bases, are impaired and the protein binds to dna in a different way, extending the contacts to the sugar-phosphate backbone.

SIGNOR-74098

O15264

Q12888

1

phosphorylation

down-regulates activity

0.2

Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif.|Dephosphorylation enables the recruitment of 53BP1 to double-strand DNA breaks |phosphorylation of T1609 is likely to be mediated by p38 MAPK

SIGNOR-264449

P28482

O60674

1

phosphorylation

down-regulates

0.513

We hypothesize that phosphorylation of ser523 in jak2 by erks 1 and/or 2 or other as-yet-unidentified kinases acts in a negative feedback manner

SIGNOR-236331

Q13882

Q12929

1

phosphorylation

up-regulates activity

0.357

Eps8 which was identified by this method is phosphorylated by Myr-PTK6 in HEK293 cells. Mouse Eps8 expressed in HEK293 cells is phosphorylated by Myr-PTK6 at residues Tyr497, Tyr524, and Tyr534. These results indicate that plasma-membrane-associated PTK6 phosphorylates Eps8, which promotes cell proliferation, adhesion, and migration and, thus, tumorigenesis.

SIGNOR-263191

P06239

P22681

0

polyubiquitination

down-regulates quantity by destabilization

0.711

Coexpression in 293T cells demonstrated that Lck kinase activity and Cbl ubiquitin ligase activity were essential for Lck ubiquitination and negative regulation of Lck-dependent serum response element-luciferase reporter activity. The Lck SH3 domain was pivotal for Cbl-Lck association and Cbl-mediated Lck degradation, with a smaller role for interactions mediated by the Cbl tyrosine kinase-binding domain.

SIGNOR-272614

Q15746

P00519

0

phosphorylation

up-regulates

0.3

Nonmuscle myosin light chain kinase (nmmlck), a multi-functional cytoskeletal protein critical to vascular homeostasis, is highly regulated by tyrosine phosphorylation. We identified multiple novel c-abl-mediated nmmlck phosphorylation sites by mass spectroscopy analysis (including y231, y464, y556, y846) and examined their influence on nmmlck function and human lung endothelial cell (ec) barrier regulation. Tyrosine phosphorylation of nmmlck increased kinase activity

SIGNOR-167989

P20336

P53611

0

lipidation

up-regulates activity

0.656

Prenylation (or geranylgeranylation) of Rab GTPases is catalysed by RGGT (Rab geranylgeranyl transferase) and requires REP (Rab escort protein). In the classical pathway, REP associates first with unprenylated Rab, which is then prenylated by RGGT. In the alternative pathway, REP associates first with RGGT; this complex then binds and prenylates Rab proteins. Rab GTPases need to be geranylgeranylated on either one or two cysteine residues in their Ctermini in order to localize to the correct intracellular membrane and be functional

SIGNOR-265575

P17612

Q9Y6D6

1

phosphorylation

up-regulates activity

0.2

Within 20 min after addition of 8-Br-cAMP, BIG1 accumulated in nuclei, and this effect was blocked by protein kinase A (PKA) inhibitors H-89 and PKI, suggesting a dependence on PKA-catalyzed phosphorylation. |Mutant BIG1 (S883A) in which Ala replaced Ser-883, a putative PKA phosphorylation site, did not move to the nucleus with cAMP addition, whereas replacement with Asp (S883D) resulted in nuclear accumulation of BIG1 without or with cAMP exposure, consistent with the mechanistic importance of a negative charge at that site

SIGNOR-272146

P35968

P48730

0

phosphorylation

down-regulates activity

0.328

CKIdelta phosphorylates VEGFR2 at both DSG and DDTD phosphodegrons to promote its interaction with beta-TRCP1.|In a reciprocal set of experiments, we found that overexpression of CKIdelta markedly decreased the half-life of VEGFR2 (XREF_FIG).

SIGNOR-280235

P27216

P46934

1

relocalization

up-regulates quantity

0.344

Annexin XIII has two known isoforms, a and b, that are apically localized, although XIIIa is also found in the basolateral compartment. In vitro binding and coprecipitation experiments showed that the Nedd4-C2 domain interacts with both annexin XIIIa and b in the presence of Ca2+, and the interaction is direct and optimal at 1 μM Ca2+.These results suggest that the apical membrane localization of Nedd4 is mediated by an association of its C2 domain with the apically targeted annexin XIIIb.

SIGNOR-272571

Q99683

Q5SGD2

0

dephosphorylation

down-regulates

0.318

Exogenous pp2cepsilon associated with exogenous ask1 in hek-293 cells under non-stressed conditions, inactivating ask1 by decreasing thr845 phosphorylation

SIGNOR-154554

P49137

Q16539

0

phosphorylation

up-regulates activity

0.769

Here we show that in vitro rk phosphorylates human gst-mapkap kinase-2 at thr25 in the proline-rich n-terminal region thr222 and ser272 in the catalytic domain and thr334 in the c-terminal domain. Using novel methodology we demonstrate that activation of mapkap kinase-2 requires the phosphorylation

SIGNOR-44351

O94953

P04637

0

transcriptional regulation

up-regulates quantity by expression

0.281

KDM4B/JMJD2B is a p53 target gene that modulates the amplitude of p53 response after DNA damage. p53 directly regulates JMJD2B gene expression by binding to a canonical p53-consensus motif in the JMJD2B promoter.

SIGNOR-263729

P35813

Q16539

1

dephosphorylation

down-regulates activity

0.408

Moreover, when expressed in mammalian cells, pp2ca inhibited the activation of the p38 and jnk cascades induced by environmental stresses. Both in vivo and in vitro observations indicated that pp2ca dephosphorylated and inactivated mapkks (mkk6 and sek1) and a mapk (p38) in the stress-responsive mapk cascades. Furthermore, a direct interaction of pp2ca and p38 was demonstrated by a co-immunoprecipitation assay

SIGNOR-59618

Q13153

P27361

0

phosphorylation

down-regulates

0.337

Activated erk can phosphorylate t292 in the prs, and this blocks the ability of pak to phosphorylate s298 and of rac-pak signaling to enhance mek1-erk complex formation.

SIGNOR-123074

Q14653

Q12899

0

polyubiquitination

down-regulates quantity by destabilization

0.672

TRIM26 bound to IRF3 and promoted its K48-linked polyubiquitination and degradation in nucleus.

SIGNOR-272440

P17302

P05129

0

phosphorylation

down-regulates activity

0.568

Phosphorylation of connexin43 on serine368 by protein kinase C regulates gap junctional communication.|These data strongly suggest that PKC directly phosphorylates Cx43 on S368 in vivo, which results in a change in single channel behavior that contributes to a decrease in intercellular communication.

SIGNOR-249050

P46531

Q8NBL1

0

glycosylation

up-regulates

0.606

O-glucosylation of epidermal growth factor-like (egf) repeats in the extracellular domain of notch is essential for notch function. A udp-glucose:protein o-glucosyltransferase (poglut/rumi) transfers o-glucose to serine within the o-glucose consensus.

SIGNOR-198713

P12931

Q13642

1

phosphorylation

up-regulates activity

0.26

However, overexpression of Src promoted most of the Flag-FHL1-WT to translocate to the nucleus, whereas the Flag-FHL1-Y149-272F mutant (phosphorylation deficient mutant) remained in the cytoplasm (XREF_FIG).|We found that Src phosphorylates FHL1 at Y149 and Y272, demonstrating that FHL1 is a bona fide novel substrate of Src.

SIGNOR-278213

Q14191

P78527

0

phosphorylation

up-regulates

0.641

Here, we identify ser-440 and -467 in wrn as major phosphorylation sites mediated by dna-pk our findings indicate that phosphorylation of ser-440 and -467 in wrn are important for relocalization of wrn to nucleoli, and that it is required for efficient dsb repair.

SIGNOR-203737

P28482

P50548

1

phosphorylation

up-regulates

0.596

The experiments presented here indicate that erf is regulated during nuclear import and/or export and that this process depends on its phosphorylation by erks our analysis indicates that in addition to t526 (position 7), s161 (position 2), s246 (position 3), and s251 (position 4) are also phosphorylated in vitro by erk2 and in vivo after mitogenic stimulation (fig. 3a).

SIGNOR-67524

O96017

Q13972

1

phosphorylation

down-regulates

0.405

During interphase, cdc25 is inhibited by ser287 phosphorylation (xenopus cdc25;ser 216 in human cdc25c) and this inhibitory phosphorylation is maintained by dna-responsive checkpoints / s287 is targeted by many kinases, including chk1, chk2, ctak-1, pka, p38 and mapkap kinase-2 suggesting that phosphorylation of this site may integrate multiple signaling inputs.

SIGNOR-150843

P01189-PRO_0000024969

P29120

0

cleavage

up-regulates quantity

0.2

POMC is post-translationally cleaved by prohormone convertase enzymes 1 and 2 (PC1, PC2) into ACTH, an N-terminal glycopeptide

SIGNOR-268724

P15172

Q12857

0

transcriptional regulation

up-regulates quantity by expression

0.246

NFIA binds to and activates the brown-fat-specific enhancers even before differentiation and later facilitates the binding of PPARgamma|NFIA has at least three functions on the transcriptional regulation of brown fat [2]. First, NFIA activates adipogenesis per se, through activating the transcription of Pparg, which encodes PPARgamma. Second, NFIA also activates the brown-fat-specific gene expression (such as Ucp1 and Ppargc1a) independent of the degree of adipocyte differentiation, through facilitating the binding of PPARgamma to the brown-fat-specific enhancers. Third, NFIA represses myogenesis through suppression of myogenic transcription factors such as Myod1 as well as Myog,

SIGNOR-263982

Q9ULT6

O60353

1

ubiquitination

down-regulates quantity

0.614

Here we show that the cell-surface transmembrane E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) and its homologue ring finger 43 (RNF43) are negative feedback regulators of Wnt signalling. ZNRF3 is associated with the Wnt receptor complex, and inhibits Wnt signalling by promoting the turnover of frizzled and LRP6.

SIGNOR-260114

Q13541

P49841

0

phosphorylation

down-regulates activity

0.364

We found that gsk-3Beta phosphorylates and inactivates 4e-bp1, thereby increasing eif4e-dependent protein synthesis. upon stimulation, 4e-bp1 is phosphorylated on several threonine and serine residues, including thr-37/46 (36). This results in dissolution of the complex, freeing eif4e to bind with mrna cap to promote translation initiation.

SIGNOR-236026

Q9ULU4

P30542

1

transcriptional regulation

up-regulates quantity by expression

0.2

We also confirmed transcriptional coactivator functions of ZMYND8 in ERα-driven reporter assays and on endogenous E2-dependent genes (Figure 5F,G). siRNA knockdown of ZMYND8 showed markedly decreased transcription at the presumptive ERα/Z3 target genes ADORA1 and NAV2, while the classical ERα targets pS2/TFF1 and GREB1 appear to be less affected (Figure 5G), suggesting likely gene-specificity of ZMYND8.

SIGNOR-266208

Q92831

Q16695

1

acetylation

down-regulates activity

0.2

The HAT module within the SAGA and ADA complexes acetylates histone H3, mainly on residues K9 and K14.

SIGNOR-269621

Q8TCQ1

P13762

1

polyubiquitination

down-regulates quantity by destabilization

0.2

Two E3 ligases, MARCH I and MARCH VIII, have been shown to polyubiquitinate lysine residue 225 in the cytoplasmic tail of I-Abeta and HLA-DRbeta. We show that lysine residue 219 in the cytoplasmic tail of DRalpha is also subject to polyubiquitination.

SIGNOR-271409

P35813

Q14164

1

dephosphorylation

down-regulates activity

0.279

PPM1A directly dephosphorylates both MAVS and TBK1 and IKKepsilon.|In a similar in vitro phosphatase assay, incubation of PPM1A also eliminated TBK1 and IKKepsilon phosphorylation at Ser 172 residue, evidenced by phospho-S172 immunoblotting (XREF_FIG, F and G).|These observations suggest that PPM1A may block kinase activities of TBK1 and IKKepsilon.

SIGNOR-277072

Q14940

P32121

0

relocalization

down-regulates activity

0.397

Internalization of the Na(+)/H(+) exchanger NHE5 into recycling endosomes is enhanced by the endocytic adaptor proteins beta-arrestin1 and -2, best known for their preferential recognition of ligand-activated G protein-coupled receptors (GPCRs)

SIGNOR-275506

P45974

Q08050

1

deubiquitination

up-regulates quantity by stabilization

0.351

Wnt signaling activation inhibits FoxM1 phosphorylation by GSK3-Axin complex and leads to interaction between FoxM1 and deubiquitinating enzyme USP5, thereby deubiquitination and stabilization of FoxM1.

SIGNOR-277210

P09211

Q05513

0

phosphorylation

up-regulates activity

0.2

Peptide phosphorylation analyses and both phosphorylation and enzyme kinetic studies with GSTP1 proteins mutated at candidate amino acid residues established Ser-42 and Ser-184 as putative phospho-acceptor residues for both kinases in the GSTP1 protein. Together, these findings show PKA- and PKC-dependent phosphorylation as a significant post-translational mechanism of regulation of GSTP1 function. Together, these results further support S42 and S184 as major phosphor-acceptor residues for PKA and PKC and suggest that the increased activity of the phospho-GSTP1 was not simply a consequence of the negative charge introduced in the GSTP1 protein by the phosphate group.All eight PKC isoforms, PKC-α, PKC-βI, PKC-βII, PKC-ε, PKC-γ, PKC-η, and PKC-ζ phosphorylated the GSTP1 protein efficiently

SIGNOR-276017

Q9Y297

Q13315

0

phosphorylation

up-regulates quantity by stabilization

0.299

ATM phosphorylates and stabilizes β-TrCP1 upon DNA damage.

SIGNOR-277549

Q15208

P38936

1

phosphorylation

down-regulates quantity by destabilization

0.2

More importantly, with the direct regulation of p21 stability by phosphorylation on Ser 146, we define here the first downstream signaling mechanisms by which NDR kinases can control G1/S progression.|NDR kinases regulate p21 stability by phosphorylation of S146 on p21. |

SIGNOR-272961

P05107

O60674

0

phosphorylation

up-regulates activity

0.265

PTKs of the JAK and SRC families have a regulatory role in LFA-1 affinity triggering, with JAKs showing a positive role (3), whereas SRCs possibly have a negative role.

SIGNOR-254738

P07948

P53396

1

phosphorylation

up-regulates activity

0.2

We demonstrate the binding of PIP2 to the CoA-binding domain of ACLY and identify the six tyrosine residues of ACLY that are phosphorylated by Lyn. Three of them (Y682, Y252, Y227) can be also phosphorylated by Src and they are located in catalytic, citrate binding and ATP binding domains, respectively. PI3K and Lyn inhibitors reduce the ACLY enzyme activity, ACLY-mediated Acetyl-CoA synthesis, phospholipid synthesis, histone acetylation and cell growth. Thus, PIP2/PIP3 binding and Src tyrosine kinases-mediated stimulation of ACLY links oncogenic pathways to Acetyl-CoA-dependent pro-growth and survival metabolic pathways in cancer cells.

SIGNOR-274105

Q15797

P36894

0

phosphorylation

up-regulates activity

0.732

Two types of bmp-induced signaling pathways are known, the smad and p38 mapk pathways. In the former case, bmpr1 phosphorylates smad-1,-5,-8, which forms a complex with smad4 that translocates into the nucleus and regulates gene expression.

SIGNOR-255263